End-stage liver disease is a major cause of mortality in the United States. Currently, liver transplantation is the only effective therapy for end-stage liver disease. An attractive therapeutic alternative is hepatocyte cell transplantation. Realizing that therapeutic potential requires understanding how hepatocyte turnover is maintained and regulated. In many tissues, the Wnt family of proteins plays a key role in regulating homeostasis by serving as niche signals to maintain tissue stem cells. We have identified a unique and novel population of hepatocytes in the liver that act as stem cells. These cells self-renew, are diploid, unlike the mostly polyploid mature hepatocytes, proliferate at a faster rate than mature hepatocytes and generate progeny that replace the entire hepatocyte population in the liver lobule over time. Importantly, these progenitors are present pericentrally in the normal liver lobule, are not dependent on injury and thereby distinct from injury-induced oval cells and Lgr5+ cells. We propose studies to further characterize these cells, determine the cellular and molecular mechanism that maintain them as progenitors and examine whether they can be expanded in culture. The results of these studies will provide a novel frame work for understanding liver homeostasis and may lead to significant advances in the use of hepatocytes for treating end-stage liver disease. The proposed studies are the core components of the Mentored Clinical Scientist Development Award (K08) for Dr. Bruce Wang. The grant is a training vehicle for Dr. Wang to achieve additional scientific training in cell culture, live imagig and hepatocyte transplantation. Also, the proposed studies will provide the critical next step in extending Dr. Wang's animal findings to human liver. To achieve these goals, Dr. Wang has devised a 5-year career development plan and assembled a multidisciplinary advisory team of scientists specializing in liver biology, endothelial cell biology and stem cell biology. The studis proposed in this grant and the ideal training environment at UCSF will ensure Dr. Wang a successful transition to an independent physician- scientist.